Differential structural requirements for fibrinogen binding to platelets and to endothelial cells.

Tranqui, L.; Andrieux, Annie; Hudry-Clergeon, G; Ryckewaert, Jean Jacques; Soyez, Serge; Chapel, Agnès; Ginsberg, Mark H.; Plow, Edward F.; Marguerie, G

doi:10.1083/jcb.108.6.2519

Cited by 67 publications

(35 citation statements)

References 54 publications

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“…It has been shown that Phe (F) as a hydrophobic binding element following the RGD sequence further enhances activity, therefore RGDF has been used as lead sequence in all of the peptides. This is in accordance with the general finding that the antiaggregatory activity of peptides following the sequence pattern RGDX decreases in the following series for X = F > V > C > Q > S [36].…”

Section: Designsupporting

confidence: 79%

Conformation/activity studies of rationally designed potent anti‐adhesive RGD peptides

Gurrath

Müller

Kessler

et al. 1992

European Journal of Biochemistry

307

225

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The Arg-Gly-Asp (RGD) sequence is a universal cell-recognition site of various extracellular proteins that interact with integrin cell-surface receptors. In order to design low-molecular-mass RGD protein antagonists, the determination of the biologically active conformation is a prerequisite. We present a method that yields detailed insight into the steric factors which govern the binding of the ligands to their receptors by systematically scanning the conformational space accessible for the tripeptide sequence RGD. The investigation is based on the conformationally controlled design of homodetic cyclic oligopeptides and their structural determination, coupled with biological assays. For this purpose, a whole set of cyclic pentapeptides and hexapeptides has been synthesized and their three-dimensional structures in solution analyzed by modern two-dimensional NMR techniques in combination with restrained and free molecular dynamics simulations. Their biological activity was compared with that of linear GRGDS in inhibition assays of tumor cell adhesion to laminin P1 and vitronectin substrates. An up to 100-fold, and in part selective, increase in activity was observed for two cyclic pentapeptides. Most other peptides showed a decreased activity which, however, was useful to correlate activity with rather small variations in conformation.Detailed comparative studies of the systematically designed conformations and the corresponding anti-adhesive activities offer an access to lead structures for a rational indirect drug design of peptide and peptidomimetic pharmaceuticals with strong interfering activity for integrin-mediated cell -cell and cell -matrix interactions.The interactions of a variety of cell-surface receptors with extracellular matrix components cause the complexity of celladhesive and cell-migratory mechanisms of several physiologically important processes including hemostasis, thrombosis, wound healing and tumor cell invasion [l]. Interactions between adhesion receptors on cell surfaces, termed integrins [2], and extracellular glycoproteins like fibrinogen, fibronectin, vitronectin and laminin form the molecular basis of cell -cell and cell -matrix contacts [3,4]. These phenomena are linked extracellularly with adhesive interactions between those substrates and their specific receptors and intracellularly with Abbreviation. cTrt, o-chlorotritylchloride; DQF, double-quantum-filtered; Fmoc, 9-fluorenylmethoxycarbonyl; HMBCS, heteronuclear multiple bond correlation with selective pulses; HMQC, heteronuclear multiple quantum coherence; inhibitory capacity (molar concentration for 50% inhibition); MD, molecular dynamics; Mtr, 4-methoxy-2,3,6-trimethylbenzenesulfonyl; NOESY, nuclear Overhauser enhancement and exchange spectroscopy; Pmc, 2,2,5,7,8-pentamethylchroman-6-sulfonyl; ROESY, rotating frame nuclear Overhauser enhancement and exchange spectroscopy; Sasrin, 2-methoxy-4-alkoxybenzylalcohol resin; TOCSY, total correlated spectroscopy. signal transduction responses [5,6]. Hence, adhesion receptors not onl...

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Section: Designsupporting

confidence: 79%

Conformation/activity studies of rationally designed potent anti‐adhesive RGD peptides

Gurrath

Müller

Kessler

et al. 1992

European Journal of Biochemistry

307

225

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“…Gel-filtered human platelets were suspended in Tyrode's buffer containing 1 mM Ca 2ϩ to a final concentration of 3 ϫ 10 8 per ml (13). Peptides were then added to the platelets up to 50 M for a 30-min incubation at 22°C, together with 300 nM 125 I-labeled fibrinogen.…”

Section: Methodsmentioning

confidence: 99%

“…The platelets were then stimulated with either 10 M ADP͞20 M epinephrine or 50 M thrombin receptor agonist peptide. After 15 min, 125 Ifibrinogen binding was measured as described (13,14). lacking the transmembrane and cytoplasmic tails of both subunits, was performed by using an immunocapture assay similar to that described (16).…”

Section: Methodsmentioning

confidence: 99%

A structural basis for integrin activation by the cytoplasmic tail of the α _IIb -subunit

Vinogradova

Haas

Plow

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

134

182

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A key step in the activation of heterodimeric integrin adhesion receptors is the transmission of an agonist-induced cellular signal from the short ␣-and͞or ␤-cytoplasmic tails to the extracellular domains of the receptor. The structural details of how the cytoplasmic tails mediate such an inside-out signaling process remain unclear. We report herein the NMR structures of a membraneanchored cytoplasmic tail of the ␣IIb-subunit and of a mutant ␣IIb-cytoplasmic tail that renders platelet integrin ␣IIb␤3 constitutively active. The structure of the wild-type ␣IIb-cytoplasmic tail reveals a ''closed'' conformation where the highly conserved N-terminal membrane-proximal region forms an ␣-helix followed by a turn, and the acidic C-terminal loop interacts with the Nterminal helix. The structure of the active mutant is significantly different, having an ''open'' conformation where the interactions between the N-terminal helix and C-terminal region are abolished. Consistent with these structural differences, the two peptides differ in function: the wild-type peptide suppressed ␣IIb␤3 activation, whereas the mutant peptide did not. These results provide an atomic explanation for extensive biochemical͞mutational data and support a conformation-based ''on͞off switch'' model for integrin activation.NMR ͉ cytoplasmic domain B y mediating numerous cell-cell and cell-matrix interactions, the integrin family of cell-surface receptors plays crucial roles in the development and health of all multicellular organisms (1-3). These noncovalent heterodimers (␣ and ␤) are expressed widely and regulate diverse biological processes such as matrix assembly, hemostasis, wound healing, inflammation, and tumor metastasis (1-3). Each subunit of an integrin consists of a single type I transmembrane domain, a large extracellular domain of several hundred amino acids, and typically, a short cytoplasmic tail of Ϸ20-70 residues (1, 2, 4). The extracellular domains interact with each other to form a complex binding site for a wide variety of ligands. Central to the function of the integrins is their capacity to undergo activation, a transition from a low to a high affinity͞avidity state for their ligands. Such activation is tightly regulated through a process termed ''insideout signaling'' (3, 4), i.e., agonist stimulation initiates intracellular changes that ultimately render the extracellular domain competent to bind ligands. The biological importance of such integrin activation is underscored by the major platelet integrin, ␣ IIb ␤ 3 , which cannot engage its abundant plasma protein ligands unless the cell has been stimulated by an agonist. This transition depends on the transmission of a cellular signal, typically initiated by occupancy of a G protein-coupled receptor, to the short cytoplasmic tails of the ␣ IIb -and͞or ␤ 3 -subunits, which is then propagated across the cell membrane to the extracellular ligandbinding domain. The structural basis of this inside-out signaling event remains poorly understood.The cytoplasmic tails of the ␣-subunits o...

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“…It is also established that the amino acid adjacent to the C-terminus of short RGD peptides alters its affinity to ¢xlIb[~3 integrin, with tryptophan and phenylalanine increasing its affinity and hydrophilic amino acids decreasing its affinity [2].…”

Section: Introductionmentioning

confidence: 99%

Importance of the structure of the RGD‐containing loop in the disintegrins echistatin and eristostatin for recognition of αIIbβ3 and αvβ3 integrins

et al. 1996

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Differential structural requirements for fibrinogen binding to platelets and to endothelial cells.

Cited by 67 publications

References 54 publications

Conformation/activity studies of rationally designed potent anti‐adhesive RGD peptides

Conformation/activity studies of rationally designed potent anti‐adhesive RGD peptides

A structural basis for integrin activation by the cytoplasmic tail of the α _IIb -subunit

Importance of the structure of the RGD‐containing loop in the disintegrins echistatin and eristostatin for recognition of αIIbβ3 and αvβ3 integrins

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Differential structural requirements for fibrinogen binding to platelets and to endothelial cells.

Cited by 67 publications

References 54 publications

Conformation/activity studies of rationally designed potent anti‐adhesive RGD peptides

Conformation/activity studies of rationally designed potent anti‐adhesive RGD peptides

A structural basis for integrin activation by the cytoplasmic tail of the α IIb -subunit

Importance of the structure of the RGD‐containing loop in the disintegrins echistatin and eristostatin for recognition of αIIbβ3 and αvβ3 integrins

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A structural basis for integrin activation by the cytoplasmic tail of the α _IIb -subunit